Modeling cancer genomic data in yeast reveals selection against ATM function during tumorigenesis

English version

Autoři: Marcel Hohl ^aff001; Aditya Mojumdar ^aff002; Sarem Hailemariam ^aff003; Vitaly Kuryavyi ^aff004; Fiorella Ghisays ^aff001; Kyle Sorenson ^aff002; Matthew Chang ^aff005; Barry S. Taylor ^aff005; Dinshaw J. Patel ^aff004; Peter M. Burgers ^aff003; Jennifer A. Cobb ^aff002; John H. J. Petrini ^aff001
Působiště autorů: Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America ^aff001; Departments of Biochemistry & Molecular Biology and Oncology, Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine; University of Calgary, Calgary, Canada ^aff002; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri, Untied States of America ^aff003; Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America ^aff004; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America ^aff005
Vyšlo v časopise: Modeling cancer genomic data in yeast reveals selection against ATM function during tumorigenesis. PLoS Genet 16(3): e32767. doi:10.1371/journal.pgen.1008422
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008422

Souhrn

The DNA damage response (DDR) comprises multiple functions that collectively preserve genomic integrity and suppress tumorigenesis. The Mre11 complex and ATM govern a major axis of the DDR and several lines of evidence implicate that axis in tumor suppression. Components of the Mre11 complex are mutated in approximately five percent of human cancers. Inherited mutations of complex members cause severe chromosome instability syndromes, such as Nijmegen Breakage Syndrome, which is associated with strong predisposition to malignancy. And in mice, Mre11 complex mutations are markedly more susceptible to oncogene -⁠ induced carcinogenesis. The complex is integral to all modes of DNA double strand break (DSB) repair and is required for the activation of ATM to effect DNA damage signaling. To understand which functions of the Mre11 complex are important for tumor suppression, we undertook mining of cancer genomic data from the clinical sequencing program at Memorial Sloan Kettering Cancer Center, which includes the Mre11 complex among the 468 genes assessed. Twenty five mutations in MRE11 and RAD50 were modeled in S. cerevisiae and in vitro. The mutations were chosen based on recurrence and conservation between human and yeast. We found that a significant fraction of tumor-borne RAD50 and MRE11 mutations exhibited separation of function phenotypes wherein Tel1/ATM activation was severely impaired while DNA repair functions were mildly or not affected. At the molecular level, the gene products of RAD50 mutations exhibited defects in ATP binding and hydrolysis. The data reflect the importance of Rad50 ATPase activity for Tel1/ATM activation and suggest that inactivation of ATM signaling confers an advantage to burgeoning tumor cells.

Klíčová slova:

Adenosine triphosphatase – DNA repair – DNA-binding proteins – Hydrolysis – Molecular dynamics – Mutation – Saccharomyces cerevisiae – Yeast and fungal models

Zdroje

1. Stracker TH, Petrini JH (2011) The MRE11 complex: starting from the ends. Nat Rev Mol Cell Biol 12 : 90–103. doi: 10.1038/nrm3047 21252998

2. Syed A, Tainer JA (2018) The MRE11-RAD50-NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair. Annu Rev Biochem 87 : 263–294. doi: 10.1146/annurev-biochem-062917-012415 29709199

3. de Jager M, Trujillo KM, Sung P, Hopfner KP, Carney JP, et al. (2004) Differential arrangements of conserved building blocks among homologs of the Rad50/Mre11 DNA repair protein complex. J Mol Biol 339 : 937–949. doi: 10.1016/j.jmb.2004.04.014 15165861

4. van der Linden E, Sanchez H, Kinoshita E, Kanaar R, Wyman C (2009) RAD50 and NBS1 form a stable complex functional in DNA binding and tethering. Nucleic Acids Res 37 : 1580–1588. doi: 10.1093/nar/gkn1072 19151086

5. Deshpande RA, Williams GJ, Limbo O, Williams RS, Kuhnlein J, et al. (2014) ATP-driven Rad50 conformations regulate DNA tethering, end resection, and ATM checkpoint signaling. EMBO J 33 : 482–500. doi: 10.1002/embj.201386100 24493214

6. Hohl M, Kwon Y, Galvan SM, Xue X, Tous C, et al. (2011) The Rad50 coiled-coil domain is indispensable for Mre11 complex functions. Nature structural & molecular biology 18 : 1124–1131.

7. Park YB, Hohl M, Padjasek M, Jeong E, Jin KS, et al. (2017) Eukaryotic Rad50 functions as a rod-shaped dimer. Nat Struct Mol Biol 24 : 248–257. doi: 10.1038/nsmb.3369 28134932

8. Hohl M, Kochanczyk T, Tous C, Aguilera A, Krezel A, et al. (2015) Interdependence of the rad50 hook and globular domain functions. Mol Cell 57 : 479–491. doi: 10.1016/j.molcel.2014.12.018 25601756

9. Al-Ahmadie H, Iyer G, Hohl M, Asthana S, Inagaki A, et al. (2014) Synthetic lethality in ATM-deficient RAD50-mutant tumors underlie outlier response to cancer therapy. Cancer Discov doi: 10.1158/2159-8290.CD-14-0380 24934408

10. Cassani C, Gobbini E, Wang W, Niu H, Clerici M, et al. (2016) Tel1 and Rif2 Regulate MRX Functions in End-Tethering and Repair of DNA Double-Strand Breaks. PLoS Biol 14: e1002387. doi: 10.1371/journal.pbio.1002387 26901759

11. Cassani C, Gobbini E, Vertemara J, Wang W, Marsella A, et al. (2018) Structurally distinct Mre11 domains mediate MRX functions in resection, end-tethering and DNA damage resistance. Nucleic Acids Res 46 : 2990–3008. doi: 10.1093/nar/gky086 29420790

12. Cassani C, Vertemara J, Bassani M, Marsella A, Tisi R, et al. (2019) The ATP-bound conformation of the Mre11-Rad50 complex is essential for Tel1/ATM activation. Nucleic Acids Res 47 : 3550–3567. doi: 10.1093/nar/gkz038 30698745

13. Stracker TH, Roig I, Knobel PA, Marjanovic M (2013) The ATM signaling network in development and disease. Front Genet 4 : 37. doi: 10.3389/fgene.2013.00037 23532176

14. Gupta GP, Vanness K, Barlas A, Manova-Todorova KO, Wen YH, et al. (2013) The mre11 complex suppresses oncogene-driven breast tumorigenesis and metastasis. Mol Cell 52 : 353–365. doi: 10.1016/j.molcel.2013.09.001 24120666

15. Cheng DT, Mitchell TN, Zehir A, Shah RH, Benayed R, et al. (2015) Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): A Hybridization Capture-Based Next-Generation Sequencing Clinical Assay for Solid Tumor Molecular Oncology. J Mol Diagn 17 : 251–264. doi: 10.1016/j.jmoldx.2014.12.006 25801821

16. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, et al. (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2 : 401–404. doi: 10.1158/2159-8290.CD-12-0095 22588877

17. Rojowska A, Lammens K, Seifert FU, Direnberger C, Feldmann H, et al. (2014) Structure of the Rad50 DNA double-strand break repair protein in complex with DNA. EMBO J doi: 10.15252/embj.201488889 25349191

18. Paull TT (2010) Making the best of the loose ends: Mre11/Rad50 complexes and Sae2 promote DNA double-strand break resection. DNA Repair 9 : 1283–1291. doi: 10.1016/j.dnarep.2010.09.015 21050828

19. Keeney S (2008) Spo11 and the Formation of DNA Double-Strand Breaks in Meiosis. Genome Dyn Stab 2 : 81–123. doi: 10.1007/7050_2007_026 21927624

20. Moore JK, Haber JE (1996) Cell cycle and genetic requirements of two pathways of nonhomologous end-joining repair of double-strand breaks in Saccharomyces cerevisiae. Mol Cell Biol 16 : 2164–2173. doi: 10.1128/mcb.16.5.2164 8628283

21. Trujillo KM, Sung P (2001) DNA structure-specific nuclease activities in the Saccharomyces cerevisiae Rad50*Mre11 complex. J Biol Chem 276 : 35458–35464. doi: 10.1074/jbc.M105482200 11454871

22. Chen L, Trujillo KM, Van Komen S, Roh DH, Krejci L, et al. (2005) Effect of amino acid substitutions in the rad50 ATP binding domain on DNA double strand break repair in yeast. J Biol Chem 280 : 2620–2627. doi: 10.1074/jbc.M410192200 15546877

23. Tseng SF, Gabriel A, Teng SC (2008) Proofreading activity of DNA polymerase Pol2 mediates 3'-end processing during nonhomologous end joining in yeast. PLoS Genet 4: e1000060. doi: 10.1371/journal.pgen.1000060 18437220

24. Keeney S, Kleckner N (1995) Covalent protein-DNA complexes at the 5' strand termini of meiosis -⁠ specific double-strand breaks in yeast. Proc Natl Acad Sci USA 92 : 11274–11278. doi: 10.1073/pnas.92.24.11274 7479978

25. Moreau S, Ferguson JR, Symington LS (1999) The nuclease activity of Mre11 is required for meiosis but not for mating type switching, end joining, or telomere maintenance. Mol Cell Biol 19 : 556–566. doi: 10.1128/mcb.19.1.556 9858579

26. Wiltzius JJ, Hohl M, Fleming JC, Petrini JH (2005) The Rad50 hook domain is a critical determinant of Mre11 complex functions. Nat Struct Mol Biol 12 : 403–407. doi: 10.1038/nsmb928 15852023

27. Regal JA, Festerling TA, Buis JM, Ferguson DO (2013) Disease-associated MRE11 mutants impact ATM/ATR DNA damage signaling by distinct mechanisms. Hum Mol Genet 22 : 5146–5159. doi: 10.1093/hmg/ddt368 23912341

28. Ivanov EL, Sugawara N, White CI, Fabre F, Haber JE (1994) Mutations in XRS2 and RAD50 delay but do not prevent mating-type switching in Saccharomyces cerevisiae. Mol Cell Biol 14 : 3414–3425. doi: 10.1128/mcb.14.5.3414 8164689

29. Mojumdar A, Sorenson K, Hohl M, Toulouze M, Lees-Miller SP, et al. (2019) Nej1 Interacts with Mre11 to Regulate Tethering and Dna2 Binding at DNA Double-Strand Breaks. Cell Rep 28 : 1564–1573 e1563. doi: 10.1016/j.celrep.2019.07.018 31390569

30. Foster SS, Balestrini A, Petrini JH (2011) Functional interplay of the Mre11 nuclease and Ku in the response to replication-associated DNA damage. Molecular and Cellular Biology 31 : 4379–4389. doi: 10.1128/MCB.05854-11 21876003

31. Mimitou EP, Symington LS (2010) Ku prevents Exo1 and Sgs1-dependent resection of DNA ends in the absence of a functional MRX complex or Sae2. The EMBO journal 29 : 3358–3369. doi: 10.1038/emboj.2010.193 20729809

32. Usui T, Ogawa H, Petrini JH (2001) A DNA damage response pathway controlled by Tel1 and the Mre11 complex. Mol Cell 7 : 1255–1266. doi: 10.1016/s1097-2765(01)00270-2 11430828

33. Yu TY, Kimble MT, Symington LS (2018) Sae2 antagonizes Rad9 accumulation at DNA double-strand breaks to attenuate checkpoint signaling and facilitate end resection. Proc Natl Acad Sci U S A 115: E11961–E11969. doi: 10.1073/pnas.1816539115 30510002

34. Hailemariam S, Kumar S, Burgers PM (2019) Activation of Tel1(ATM) kinase requires Rad50 ATPase and long nucleosome-free DNA, but no DNA ends. J Biol Chem doi: 10.1074/jbc.RA119.008410 31073030

35. Bonetti D, Villa M, Gobbini E, Cassani C, Tedeschi G, et al. (2015) Escape of Sgs1 from Rad9 inhibition reduces the requirement for Sae2 and functional MRX in DNA end resection. EMBO Rep 16 : 351–361. doi: 10.15252/embr.201439764 25637499

36. Oh J, Lee SJ, Rothstein R, Symington LS (2018) Xrs2 and Tel1 Independently Contribute to MR-Mediated DNA Tethering and Replisome Stability. Cell Rep 25 : 1681–1692 e1684. doi: 10.1016/j.celrep.2018.10.030 30428339

37. Lee JH, Mand MR, Deshpande RA, Kinoshita E, Yang SH, et al. (2013) Ataxia telangiectasia-mutated (ATM) kinase activity is regulated by ATP-driven conformational changes in the Mre11/Rad50/Nbs1 (MRN) complex. J Biol Chem 288 : 12840–12851. doi: 10.1074/jbc.M113.460378 23525106

38. Liu Y, Sung S, Kim Y, Li F, Gwon G, et al. (2016) ATP-dependent DNA binding, unwinding, and resection by the Mre11/Rad50 complex. EMBO J 35 : 743–758. doi: 10.15252/embj.201592462 26717941

39. Lim HS, Kim JS, Park YB, Gwon GH, Cho Y (2011) Crystal structure of the Mre11-Rad50-ATPgammaS complex: understanding the interplay between Mre11 and Rad50. Genes Dev 25 : 1091–1104. doi: 10.1101/gad.2037811 21511873

40. Hopfner KP, Karcher A, Shin DS, Craig L, Arthur LM, et al. (2000) Structural biology of Rad50 ATPase: ATP-driven conformational control in DNA double-strand break repair and the ABC-ATPase superfamily. Cell 101 : 789–800. doi: 10.1016/s0092-8674(00)80890-9 10892749

41. Foster SS, De S, Johnson LK, Petrini JH, Stracker TH (2012) Cell cycle -⁠ and DNA repair pathway-specific effects of apoptosis on tumor suppression. Proceedings of the National Academy of Sciences of the United States of America 109 : 9953–9958. doi: 10.1073/pnas.1120476109 22670056

42. Paull TT (2015) Mechanisms of ATM Activation. Annu Rev Biochem 84 : 711–738. doi: 10.1146/annurev-biochem-060614-034335 25580527

43. Usui T, Petrini JH, Morales M (2006) Rad50S alleles of the Mre11 complex: questions answered and questions raised. Exp Cell Res 312 : 2694–2699. doi: 10.1016/j.yexcr.2006.06.013 16857186

44. Gobbini E, Villa M, Gnugnoli M, Menin L, Clerici M, et al. (2015) Sae2 Function at DNA Double-Strand Breaks Is Bypassed by Dampening Tel1 or Rad53 Activity. PLoS Genet 11: e1005685. doi: 10.1371/journal.pgen.1005685 26584331

45. Lee JH, Paull TT (2005) ATM Activation by DNA Double-Strand Breaks Through the Mre11-Rad50-Nbs1 Complex. Science 308 : 551–554. doi: 10.1126/science.1108297 15790808

46. Williams GJ, Williams RS, Williams JS, Moncalian G, Arvai AS, et al. (2011) ABC ATPase signature helices in Rad50 link nucleotide state to Mre11 interface for DNA repair. Nat Struct Mol Biol 18 : 423–431. doi: 10.1038/nsmb.2038 21441914

47. Boswell ZK, Canny MD, Buschmann TA, Sang J, Latham MP (2019) Adjacent mutations in the archaeal Rad50 ABC ATPase D-loop disrupt allosteric regulation of ATP hydrolysis through different mechanisms. Nucleic Acids Res doi: 10.1093/nar/gkz1228 31889185

48. Lee K, Zhang Y, Lee SE (2008) Saccharomyces cerevisiae ATM orthologue suppresses break-induced chromosome translocations. Nature 454 : 543–546. doi: 10.1038/nature07054 18650924

49. Halazonetis TD, Gorgoulis VG, Bartek J (2008) An oncogene-induced DNA damage model for cancer development. Science 319 : 1352–1355. doi: 10.1126/science.1140735 18323444

50. Kim JH, Penson AV, Taylor BS, Petrini JHJ (2019) Nbn-Mre11 interaction is required for tumor suppression and genomic integrity. Proc Natl Acad Sci U S A 116 : 15178–15183. doi: 10.1073/pnas.1905305116 31285322

51. Schoppy DW, Ragland RL, Gilad O, Shastri N, Peters AA, et al. (2012) Oncogenic stress sensitizes murine cancers to hypomorphic suppression of ATR. J Clin Invest 122 : 241–252. doi: 10.1172/JCI58928 22133876

52. Ferrari M, Dibitetto D, De Gregorio G, Eapen VV, Rawal CC, et al. (2015) Functional interplay between the 53BP1-ortholog Rad9 and the Mre11 complex regulates resection, end-tethering and repair of a double-strand break. PLoS Genet 11: e1004928. doi: 10.1371/journal.pgen.1004928 25569305

53. Hoffman CS (2001) Preparation of yeast DNA. Curr Protoc Mol Biol Chapter 13: Unit13 11.

54. Chan SW, Chang J, Prescott J, Blackburn EH (2001) Altering telomere structure allows telomerase to act in yeast lacking ATM kinases. Curr Biol 11 : 1240–1250. doi: 10.1016/s0960-9822(01)00391-8 11525738

55. Benson DA, Cavanaugh M, Clark K, Karsch-Mizrachi I, Lipman DJ, et al. (2013) GenBank. Nucleic Acids Res 41: D36–42. doi: 10.1093/nar/gks1195 23193287

56. Jones S, van Heyningen P, Berman HM, Thornton JM (1999) Protein-DNA interactions: A structural analysis. J Mol Biol 287 : 877–896. doi: 10.1006/jmbi.1999.2659 10222198

57. Buchan DW, Minneci F, Nugent TC, Bryson K, Jones DT (2013) Scalable web services for the PSIPRED Protein Analysis Workbench. Nucleic Acids Res 41: W349–357. doi: 10.1093/nar/gkt381 23748958

58. Schrödinger LLC NY, NY, 2019 (2019).

59. Seifert FU, Lammens K, Hopfner KP (2015) Structure of the catalytic domain of Mre11 from Chaetomium thermophilum. Acta Crystallogr F Struct Biol Commun 71 : 752–757. doi: 10.1107/S2053230X15007566 26057807

60. Waterhouse A, Bertoni M, Bienert S, Studer G, Tauriello G, et al. (2018) SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res 46: W296–W303. doi: 10.1093/nar/gky427 29788355

61. Ismer J, Rose AS, Tiemann JK, Goede A, Preissner R, et al. (2016) SL2: an interactive webtool for modeling of missing segments in proteins. Nucleic Acids Res 44: W390–394. doi: 10.1093/nar/gkw297 27105847

62. D. E. Shaw Research NY, NY, 2019.

63. Martyna GJ, Klein ML, Tuckerman M (1992) Nose-Hoover Chains—the Canonical Ensemble Via Continuous Dynamics. Journal of Chemical Physics 97 : 2635–2643.

64. Martyna GJ (1994) Remarks on "Constant-temperature molecular dynamics with momentum conservation". Phys Rev E Stat Phys Plasmas Fluids Relat Interdiscip Topics 50 : 3234–3236. doi: 10.1103/physreve.50.3234 9962369

65. Ruff P, Donnianni RA, Glancy E, Oh J, Symington LS (2016) RPA Stabilization of Single-Stranded DNA Is Critical for Break-Induced Replication. Cell Rep 17 : 3359–3368. doi: 10.1016/j.celrep.2016.12.003 28009302

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